DTI-derived evaluation of glymphatic system function in Veterans with chronic multisymptom illness

Abstract:BACKGROUND AND PURPOSE: Chronic multisymptom illness (CMI) includes symptoms of fatigue, pain, and sleep difficulties, as well as neurologic, respiratory, and gastrointestinal problems and is particularly common in veterans from the 1990–1991 Gulf War and the Afghanistan and Iraq Wars. Glymphatic system function may play an important role in the etiopathology of CMI but has not been addressed. DTI-derived analysis along the perivascular space provides a promising proxy for glymphatic system function by evaluating the status of perivascular space fluid flow. The objective of this study was to compare this DTI-derived glymphatic index in veterans with CMI and healthy controls, and to reveal possible correlations between this index and the severity of CMI symptoms. MATERIALS AND METHODS: DTI-derived indices were extracted from imaging data of 203 veterans who met clinical diagnostic criteria for CMI, and 224 age-matched healthy control subjects from multiple public research databases. Severity of CMI, sleep difficulty, pain intensity, and the degree of chronic fatigue were based on self-report measures. MRI scanner and site variations were harmonized. Statistical analyses were performed adjusting for demographic confounding factors. RESULTS: Both healthy controls and veterans showed significantly reduced glymphatic indices associated with increased age. Compared with controls, veterans showed bilaterally lower indices (Cohen d = −0.47; P < .001) after adjusting for age, sex, and education. Across the entire sample of veterans, negative correlations were observed between glymphatic indices and pain intensities (r = −0.17; P = .01), sleep disturbances (r = −0.17; P = 0.02), degree of fatigue (r = −0.20; P = 0.006), severity of CMI (r = −0.17; P = 0.02), and the indices were positively correlated with medullar volumes (r = −0.19; P = .007). Note, these results showing significant outcomes for a group of patients do not guarantee the same outcome for individual patients. CONCLUSIONS: This study suggests that impaired glymphatic functions are strongly associated with CMI. These findings improve our understanding of the pathologic mechanism underlying CMI and point to DTI-based metrics as a potential biomarker for disease severity in this condition.